Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. Following initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic. Chronic hepatitis can progress to liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. This and the number of patients involved, has made HCV the focus of considerable medical research. Replication of the genome of HCV is mediated by a number of enzymes, amongst which is HCV NS3 serine protease and its associated cofactor, NS4A. NS3 serine protease is considered to be essential for viral replication and has become an attractive target for drug discovery.
Current anti-HCV therapy is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. Not only does this therapy result in a limited efficacy in that only part of the patients are treated successfully, but it also faces significant side effects and is poorly tolerated in many patients. Hence there is a need for further HCV inhibitors that overcome the disadvantages of current HCV therapy such as side effects, limited efficacy, poor tolerance, the emergence of resistance, as well as compliance failures.
Various agents have been described that inhibit HCV NS3 serine protease. WO 05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentyl moiety. Amongst these, the macrocyclic derivatives are attractive by overcoming one or more of the disadvantages of current anti-HCV therapy.
It has been found that the compound of formula (I), with the structure depicted hereafter, is particularly suited for use in anti-HCV therapy:

The compound of formula (I) is an inhibitor of the Hepatitis C virus (HCV) serine protease and is described in WO 2007/014926, published on 8 Feb. 2007. This compound overcomes several of the disadvantages of current anti-HCV therapy and in particular shows pronounced activity against HCV, has an attractive pharmacokinetic profile, and is well-tolerated. Following the synthesis procedure described in Example 5 of WO 2007/014926, an amorphous solid form is obtained.
It now has been found that the compound of formula (I) can be converted into crystalline forms, which can advantageously be used as active ingredients in anti-HCV therapy. To that purpose, these crystalline forms are converted into pharmaceutical formulations.
An amorphous form is a form in which a three-dimensional long-range order does not exist. In the amorphous form the position of the molecules relative to one another are essentially random, i.e. without regular arrangement of the molecules in a lattice structure. Amorphous materials may have interesting properties, but generating and stabilising this state usually offers difficulties in that the crystalline state typically is the more stable state. Compounds in amorphous form can convert partially or completely to crystalline forms over time or under the influence of external factors such as temperature, humidity, traces of crystalline material in the environment, etc. Usually a crystalline form of an active ingredient is preferred in the manufacture and storage of pharmaceutical dosage forms.
A crystal or crystalline form is the form in which the position of the molecules relative to one another is organised according to a three-dimensional lattice structure. Crystalline forms may include polymorphs and pseudopolymorphs. Polymorphs are different crystalline forms of the same compound resulting from a different arrangement of the molecules in the solid state. Polymorphs differ from each other in their physicochemical properties but not in their chemical composition. Polymorphism can be difficult to control and may pose challenges to the development of pharmaceutical dosage forms. The term pseudopolymorphs refers to different crystal forms due to different amounts or types of solvent in the lattice structure of a compound.
Solid state chemistry is of interest to the pharmaceutical industry, in particular as concerns the development of suitable dosage forms. Solid state transformations may seriously impact the stability of pharmaceuticals (shelf-life). A metastable pharmaceutical solid form can change into a crystalline structure (e.g. from amorphous to crystalline) or solvate/desolvate in response to changes in environmental conditions, processing, or over time.
Different crystal forms or the amorphous form of a given drug may have substantial differences in such pharmaceutically important properties as dissolution rate, thermodynamic solubility, and bioavailability. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the patient's bloodstream. The rate of dissolution is thus a consideration in formulating solid and liquid dosage forms. Likewise, different solid forms may have different processing properties, such as hygroscopicity, flowability, compactation, and the like, which could affect their suitability as active pharmaceuticals for commercial production.
During the clinical development of pharmaceutical drugs, if the polymorphic form is not held constant, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations.
It is an object of the present invention to provide the HCV inhibitory agent of formula (I) in a crystalline form having beneficial properties in terms of one or more of the following: the ability to be formulated, to be stored and to be administered as to effectively excert its antiviral properties.